Fibrosis is the common scarring reaction associated with chronic injury that results from prolonged parenchymal cell injury and/or inflammation that may be induced by a wide variety of agents, e.g., drugs, toxins, radiation, any process disturbing tissue or cellular homeostasis, toxic injury, altered blood flow, infections (viral, bacterial, spirochetal, and parasitic), storage disorders, and disorders resulting in the accumulation of toxic metabolites. Fibrosis is most common in the heart, lung, peritoneum, and kidney.
For instance, hepatic fibrosis (liver fibrosis) results from an altered wound healing response that is characterized by increased production of matrix proteins and decreased matrix remodeling. Normal structural elements of tissues are replaced with excessive amounts of non-functional scar tissue. Hepatic fibrosis is a common pathological consequence of chronic liver diseases. Examples of such chronic liver diseases include chronic hepatitis B and C virus infections, alcoholic liver disease, non-alcoholic steatohepatitis (NASH) and autoimmune liver disease. In a number of patients, fibrosis ultimately leads to cirrhosis, a condition defined by an abnormal liver architecture, with fibrotic septa surrounding regenerating nodules and altered vacularization. Due to decreased functional parenchymal reserve and altered hepatic blood flow, cirrhosis is associated with the life-threatening complications of liver failure including hepatic encephalopathy, coagulation disorders and bacterial infections, and complications of portal hypertension such as ascites, variceal rupture and hepatorenal syndrome. In addition, the cirrhotic liver is a precancerous state, and thus requires the systematic screening for hepatocellular carcinoma. Several clinical reports have documented that regression of liver fibrosis occurs in a substantial proportion of patients, provided that the factor responsible for liver insult is eradicated or controlled (7, 16, 57). Consistent with this observation, studies in rodents have also documented regression of fibrosis or early stage cirrhosis within weeks following eradication of the toxic insult. The potential for reversibility of fibrosis declines at advanced stages. It is imperative to treat fibrosis in the early stages of reversible liver scarring so that irreversible cirrhosis can be prevented.
Monoglyceride Lipase (MGL) is a target known in the art and first identified by Wall et al. (Virus Res. 1997, 52, 152-167) in 1997 and designated HUKS. Dinh et al. (Proc. Nat. Acad. Sci., 2002, 99, 10819-10824) found that the rat MGL participates in inactivation of 2-arachidonoylglycerol (2-AG), an endogenous cannabinoid monoglyceride. It is highly expressed in regions of rat brain that also express cannabinoid receptors and it appears to assume a presynaptic localization in the hippocampus. MGL inhibitors are therefore potentially useful for the treatment of pain, inflammation, and CNS disorders. In addition to the brain, MGL is expressed in adipocytes, where it functions together with hormone-sensitive lipase (LIPE) to hydrolyze intracellular triglyceride stores, and in the intestine, where it is largely responsible for cleaving monoacyglycerols to form free fatty acids and glycerol. These observations implicate MGL in metabolic diseases and suggest that MGL inhibitors will have beneficial effects on metabolic disorders, including obesity, hyperphagia and diabetes. The effect of MGL inhibitors for the treatment of fibrosis has never been investigated in the prior art.